Process for preparing 2-amino-1,4-dihydropyridine derivates

ABSTRACT

2-Amino-1,4-dihydropyridines bearing a carbonyl function in the 5-position and being optionally substituted by lower alkyl or phenyl in the 6-position, and the corresponding 2-amino1,4,5,6,7,8-hexahydro-5-oxoquinolines, which derivatives are further substituted by a carbonyl group in the 3-position and optionally substituted in the 4-position by lower alkyl, phenyl, substituted phenyl or a heterocyclic group are antihypertensive agents and coronary vessel dilators. The compounds, of which 2amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5dicarboxylic acid 3,5-diethyl ester is a representative embodiment, are prepared through condensation of an ylideneacetoacetic acid ester and an amidine.

United States Patent 1191 Meyer et al.

llll 3,919,246

[ 1 Nov. 11, 1975 [73] Assignee: Bayer Aktiengesellschaft, Germany {22]Filed: Oct. 17, 1974 [ll] Appl. No: 515,640

Related US. Application Data [62] Di\ision of Ser. No. 336.639. Feb. 28.l973. Pat. No.

[30] Foreign Application Priority Data Mar. 6. I972 Germany 2210674 [52]US. Cl. ..260/294.9; 260/294.8 F;

260/2948 G; 260/2955 A; 260/2955 B; 260/2955 R; 424/266 l| Int. Cl.-'.C07D 213/55 81 Field of Search .260/2955 R, 295.5 B. 294.8 F, 260/2948G. 295.5 A

[56] References Cited UNITED STATES PATENTS 3.799.934 3/l974 Meyer etal. Natl/295.5 R

Primary E,\u/n/nerAlan L. Rotmun [57] ABSTRACTZ-Amino-l.4dihyclropyridines bearing a carbonyl function in the5-position and being optionally substituted by lower alkyl or phenyl inthe 6-position, and the corresponding Z-amino-l45.6.7.8-hexahydro-5-oxoquinolines. which derivatives are further substituted by a carbonylgroup in the 3-position and up tionally substituted in the 4-position bylower alkyl. phenyl substituted phenyl or a heterocyelic group areantihypertensive agents and coronary vessel dilators. The compounds. ofwhich 2 z1mino-6methyl-4-(3- nitrophenyl l.4-dihydropyridine-3.5-dicarboxylic acid 3.5-diethyl ester is arepresentative embodiment. are prepared through condensation of anylideneacetoacetic acid ester and an amidine.

35 Claims. No Drawings PROCESS FOR PREPARING Z-AMINO-1,4-DIHYDROPYRIDINEDERIVATES This is a div. of app. Ser. No. 336,639 filed Feb. 28, l973now US. Pat. No. 3,867,393.

The present invention pertains to Z-amino-lA-dihydropyridinederivatives. to processes for their production and use and topharmaceutical compositions containing such compounds and useful asantihypertensive agents and coronary vessel dilators.

in particular. the present invention pertains to compounds of theformula i l R 11 R20 c11 I N \NH2 wherein R is hydrogen; lower alkyl',lower alkenyl; lower alkynyl; phenyl; substituted phenyl in which thesubstituents are one to three members selected from the group consistingof lower alkyl, lower alkoxy, halogeno, nitro, cyano, trifluoromethyl,azido, carbo(lower alkoxy), lower alkylsulfonyl, lower alkylsulfinyl,lower alkylthio or phenyl; naphthyl; or a heterocyclic ring selectedfrom the group consisting of quinolyl, isoquinolyl, pyridyl, pyrimidyl,thenyl, fury] and pyrryl, said heterocyclic ring being unsubstituted orsubstituted by one or two members selected from the group consisting oflower alkyl, lower alkoxy and halogeno;

R, when taken independently, is hydrogen, lower alkyl, phenyl orpyridyl;

R when taken independently, is lower alkyl, lower alkoxy, lower alkoxy(lower alkoxy), lower alkenyloxy, lower alkynyloxy, amino, loweralkylamino or di( lower alkyl)amino,

R and R when taken together are alkylene of two to four carbon atoms;and

R is lower alkyl, lower alkoxy, lower alkoxy(lower alkoxy), loweralkenyloxy, lower alkynyloxy, amino, lower alkylamino or di(loweralkyl)amino.

The term lower alkyl denotes a univalent saturated branched or straighthydrocarbon chain containing from one to six carbon atoms.Representative of such lower alkyl groups are thus methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec.butyl, tertbutyl, pentyl,isopentyl, neopentyl, tert.pentyl, hexyl, and the like.

The term lower alkenyl denotes a univalent branched or straighthydrocarbon chain containing from two to six carbon atoms andnonterminal ethylenic unsaturation as, for example. vinyl, allyl,isopropenyl, 2-butenyl, 3-methyl-2-butenyl, Z-pentenyl, 3-pentenyl,Z-hexenyl, 4-hexenyl, and the like.

The term lower alkynyl denotes a univalent branched or straighthydrocarbon chain containing from two to six carbon atoms andnonterminal acetylenic unsaturation as, for example, ethynyl,Z-propynyl, 4-pentynyl, and the like,

The term lower alkoxy denotes a straight or branched hydrocarbon chainbound to the remainder of the mol- 2 ecule through an ethereal oxygenatom as, for example. methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, pentoxy and hexoxy.

The term lower alkylthio denotes a branched or straight hydrocarbonchain bound to the remainder of the molecule through a divalent sulfuras, for example. methylthio, ethylthio, propylthio, isopropylthio,butylthio, and the like.

The term halogen denotes the substituents fluoro, chloro, bromo andiodo.

As indicated, the present invention also pertains to the physiologicallyacceptable non-toxic acid addition salts of these basic compounds. Suchsalts include those derived from organic and inorganic acids such as,without limitation, hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid, methane sulphonic acid. acetic acid, tartaric acid,lactic acid, succinic acid. citric acid, malic acid, maleic acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, embonic acid,enanthic acid, and the like.

According to the present invention, the foregoing compounds are preparedby reacting a dicarbonyl compound of the formula:

wherein R, R and R are as herein defined, with an amidine of theformula:

in which R is as herein defined. The condensation proceeds smoothly ingood yields simply by heating the two components, generally in thepresence of an inert organic solvent such as methanol, ethanol, propanoland similar alkanols, ethers such as dioxane and diethyl ether, glacialacetic acid, pyridine, dimethylformamide, dimethylsulfoxide,acetonitrile and the like. The reaction is conducted at temperatures offrom 20 to 250C, conveniently at the boiling point of the solvent, andwhile elevated pressure may be utilized, normal atmospheric pressure isgenerally satisfactory. The reactants are employed in substantiallyequimolar amounts. The

amidine reactant can be employed as the free base or in.

the form of a salt such as the hydrohalide salts with the amidine beingliberated from the salt through treatment with a basic agent such as analkali metal alkoxide. The dicarbonyl reagent can be utilized as such orgenerated in situ by the reaction of an aldehyde of the formula RCHO anda ,B-dicarbonyl compound of the formula RCOCH- COR It is rathersurprising that the above described condensation produces the desiredcompounds in such good yields and with such high purity for while it isknown that a benzylide neacetoacetic acid ester can be condensed withamino crotonic acid ester to yield a l,4-dihydropyridine (Knoevenagel,Ber. 31, 743, I898), it would be expected from, for example,Silversmith, J. Org. Chem. 27, 4090 1952) that the addition of anamidine to an a,B-unsaturated keta compound would yield thedihydropyrimidine derivative rather than the dihydropyridine derivative.

Many of the dicarbonyl compounds utilized as one of the reactants areknown to the art and the others can either be generated in situ asherein described or prepared according to methods well known to the art.see for example Org. Reaction XV. 204 et seq. (1967). Typical of thisreactant are the following compounds:

benzylideneacetoacetic acid methyl ester, ethylideneacetoacetic acidmethyl ester. isopropylideneacetoacetic acid methyl ester.2-nitrobenzylideneacetoacetic acid methyl ester.Z-nitrobenzylideneacetylacetone. benzylideneacetylacetone.3-nitrobenzylideneacetoacetic acid methyl ester.3-nitrobenzylideneacetoacetic acid propargyl ester.3-nitrobenzylideneacetoacetic acid allyl ester.3-nitrobenzylideneacetoacetic acid B-methoxyethyl ester.3-nitrobenzylideneacetoacetic acid B-ethoxyethyl ester.3-nitrobenzylideneacetoacetic acid isopropyl ester,3-nitrobenzylideneacetylacetone. 4-nitrobenzylideneacetylacetone.4-nitrobenzylideneacetoacetic acid B-propoxyethyl ester.4-nitrobenzylideneacetoacetic acid n-propyl ester.3-nitro-6-chlorobenzylideneacetoacetic acid methyl ester.2-cyanobenzylideneacetoacetic acid methyl ester,Z-cyanobenzylideneacetoacetic acid methyl ester,2-cyan0benzylideneacetoacetic acid ethyl ester.2-cyanobenzylidenepropionylacetic acid ethyl ester.3-cyanobenzylideneacetoacetic acid methyl ester.3-nitro-4-chlorobenzylideneacetylacetone.3-nitro-4-chlorobenzylideneacetoacetic acid t-butyl ester.3-nitr0-4-chlorobenzylideneacetoacetic acid methyl ester.2-nitro-4-methoxybenzylideneacetoacetic methyl ester.2-cyano-4-methylbenzylideneacetoacetic acid ethyl ester.2-azidobenzylideneacetoacetic acid ethyl ester.3-azidobenzylideneacetylacetone. Z-methylmercaptobenzylideneacetoaceticacid isopropyl ester. 2-sulphinylmethylbenzylideneacetoacetic acid ethylester. 2-sulphonylbenzylidenemethylacetoacetic acid allyl ester.4-sulphonylmethylbenzylideneacetoacetic acid ethyl ester.naphth-l-ylideneacetoacetic acid methyl ester.naphth-l-ylideneacetoacetic acid ethyl ester.naphth-2-ylideneacetoacetic acid ethyl ester.Z-ethoxynaphth-l-ylideneacetoacetic acid methyl ester.Z-methoxynaphth-l-ylideneacetoacetic acid ethyl ester.S-bromonaphth-l-ylideneacetoacetic acid methyl ester.quinol-2-ylmethylideneacetoacetic acid methyl ester.quinol-3-ylmethylideneacetoacetic acid methyl ester.quinol-4-ylmethylideneacetoacetic acid ethyl ester.quinol-S-ylmethylideneacetoacetic acid ethyl ester.isoquinol-l-ylmethylideneacetoacetic acid methyl acidisoquinol-3-ylmethylideneacetoacetic acid methyl ester.

4 a-pyridylmcthylideneacetoacetic acid methyl ester.oz-pyridylmethylideneacetoacetic acid ethyl ester.a-pyridylmethylideneacetoacetic acid allyl ester.a-pyridylmethylideneacetoacetic acid cyclohexyl ester.

B-pyridylmethylideneacetoacetic yethyl ester.

y-pyridylmethylideneacetoacetic acid methyl ester.

fi-methyl-a-pyridylmethylideneacetoacetic acid ethyl ester.

4.6-dimethoxypyrimid-S-ylmethylideneacetoacetic acid ethyl ester.

then-2-ylmethylideneacetoacetic acid ethyl ester.

fur-2-ylmethylideneacetoacetic acid allyl ester.

pyrr-Z-ylthylideneacetoacetic acid methyl ester.

nitrobenzyIidenepropionylacetic acid ethyl ester.

a-pyridylmethylidenepropionylacetic acid ethyl ester.

a-pyridylmethylidenepropionylacetic acid methyl ester.

a-pyridylmethylideneacetylacetone.

2-. 3- or 4-methoxybe nzylideneacetoacetic acid ethyl ester.

2-. 3- or 4-meth0xybenzylideneacetylacetone.

2-methoxybenzylideneacetoacetic acid allyl ester.

Z-methoxybenzylideneacetoacetic acid allyl ester.

Z-methoxybenzylideneacetoacetic acid propargyl ester.

2-methoxybenzylideneacetoacetic acid B-methoxyethyl ester.

2-isopropoxybenzylideneacetoacetic acid ethyl ester.

3-butoxybenzylideneacetoacetic acid methyl ester,

3.4.5-trimethoxybenzylideneacetoacetic acid allyl ester.

Z-methylbenzylidenepropionylacetic acid methyl ester.

2-. 3- or 4-methylbenzylideneacetoacetic acid ethyl ester.

2-methylbenzylideneacetoacetic yethyl ester.

2-methylbenzylideneacetoacetic acid B-propoxyethyl ester.

2-methylbenzylideneacetylacetone.

3.4-dimethoxy-5-br0mobenzylideneacetoacetic acid ethyl ester.

2-. 3- or 4-chlorobenzylideneacetoacetic acid ethyl ester. 2-. 3- or4-bromobenzylideneacetoacetic acid ethyl ester.

2-. 3- or 4-fluorobenzylideneacetoacetic acid ethyl ester.

2-fluorobenzylideneacetoacetic acid methyl ester.

3-chlorobenzylideneacetylacetone.

3-chlorobenzylidenepropionylacetic acid ethyl ester.3-chl0r0benzylideneacetoacetic acid ethyl ester.2-chlorobenzylideneacetoacetic acid allyl ester.

2-. 3- or 4-trifluor0methylbenzylideneacetoacetic acid isopropyl ester.

3-trifluoromethylbenzylideneacetoacetic acid methyl ester.

2-carbethoxybenzylid eneacetoacetic acid ethyl ester.

3-carbomethoxybenzylideneacetoacetic acid methyl ester.

4-carboisopropoxybenzylideneacetoacetic acid isopropyl ester.

4-carbomethoxybenzylideneacetoacetic acid allyl ester.

3-nitrobenzylidenecyclohexanel .3-dione. and

3-nitrobenzylidenecycloheptane-l .3-dione.

acid B-methoxacid B-methox- The amidine reactants are similarly known orcan be readily produced according to known methods, see for exampleMcElvain et al.. J.A.C.S., 73, 2760 (195l). Typical of these reactantsare the following:

amidinoacetic acid methyl ester.

amidinoacetic acid ethyl ester,

amidinoacetic acid n-propyl ester.

amidinoacetic acid isopropyl ester,

amidinoacetic acid cyclohexyl ester.

amidinoacetic acid B-methoxyethyl ester.

amidinoacetic acid a-ethoxyethyl ester.

amidinoacetic acid B-ethoxyethyl ester, amidinoacetic acid propargylester, and amidinoacetamide.

As noted above. the compounds of the present invention demonstrate theability to reduce blood pressure and to effect a dilation of thecornonary vessels. They can accordingly be used where either or both ofthese effects are desired. Thus upon parenteral oral or sublingualadministration, the compounds produce a distinct and long lastingdilation of the coronary vessels which is intensified by a simultaneousnitritelike effect of reducing the load on the heart. The effect onheart metabolism is thus one of energy saving. In addition, thecompounds lower the blood pressure of normotonic and hypertonic animalsand can thus be used as antihypertensive agents. These properties can beconveniently observed in well known laboratory models. Thus for examplethe coronary vessel dilation effect can be observed by measuring theincrease in oxygen saturation in the coronary sinus in the narcotized.heart catheterized dog. as shown in the following table:

I.\'. Dose (mg/kg) -continued Compound Dose (mg/kg) Z-amino-h-methyll,(I dihydropyridinel diethyl ester 44 Z-cyanopheny l J- l .4- 5-di-arhoxy lic acid Z-aminotv-methyl--44 Z-trlfluoromethy I- ll) pheny l ll.J-dihy dropyridine-3 .S-dicarhoxylic acid diethyl ester The toxicity ofthe compounds is remarkably low. Thus for example the toxic dose of2-amino-6-methyl- 4-( Z-trifluoromethylphenyl l .4-dihydropyridine-3 .5-dicarboxylic acid diethyl ester in mice upon oral administration isgreater than l.000 mg/kg.

In addition to the effect on blood pressure and coronary vessels thecompounds also lower the excitability of the stimulus formation andexcitation conduction Return to normal 0 values (hours!Z-amino-o-methyl- (H11 44 3-nitropheny l l.4-dihy dropridine-3.5-dicarhosylic acid diethyl ester The hypotensive activity ofthe present compounds can be observed by measuring the blood pressure ofhypertensive rats following administration of the compounds. Thefollowing table demonstrates the dose which results in at least a l 5 mmHg reduction in blood pressure of such animals:

Compound Dose lmg/kg) system within the heart so that anantifibrillation action is observed at therapeutic doses. The tone ofthe smooth muscle of the vessels is also greatly reduced. Thisvascular-spasmolytic action can be observed in the entire vascularsystem as well as in more or less isolated and circumscribed vascularregions such as the central nervous system. In addition. a strongmuscular-spasmolytic action is manifested in the smooth muscle of thestomach. the intestinal tract, the urogenital tract and the respiratorysystem. Finally. there is some evidence that the compounds influence thecholesterol level and lipid level of the blood. These effects complementone another and the compounds are thus highly desirable aspharmaceutical agents to be used in the treatment of hypertension andconditions characterized by a constriction of the coronary bloodvessels.

Pharmaceutical compositions for effecting such treatment will contain amajor or minor amount, e.g. from 95 to 0.5%, of at least one2-amino-l.4-dihydropyridine as herein defined in combination with apharmaceutical carrier, the carrier comprising one or more solid,semi-solid or liquid diluent, filler and formulation adjuvant which isnontoxic, inert and pharmaceutically acceptable. Such pharmaceuticalcompositions are preferably in dosage unit form; i.e.. physicallydiscrete units containing a predetermined amount of the drugcorresponding to a fraction or multiple of the dose which is calculatedto produce the desired therapeutic response. The dosage units cancontain one. two, three four or more single doses or. alternatively.one-half, third or fourth of a single dose. A single dose preferablycontains an amount sufficient to produce the desired therapeutic effectupon administration at one application of one or more dosage unitsaccording to a predetermined dosage regimen, usually a whole, half,third or quarter of the daily dosage administered once, twice, three offour times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient. the route of administration andthe nature and gravity of the illness, generally the daily dose will befrom about 0.00l to about 2 mg/kg, preferably 0.005 to 1.0 mg/kg, whenadministered parenterally and from about 0.1 to about mg/kg, preferably0.5 to ID mg/kg, when administered orally. In some instances asufficient therapeutic effect can be obtained at lower doses while inothers, larger doses will be required.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc. magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl cellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaoline or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup. starch paste, acacia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating. the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt. talc ormineral oil. The lubricated mixture is then compressed into tablets. Themidicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing cost of she]- lac, a coating of sugar or polymeric material anda polish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous sucrose solution while elixirsare prepared through the use of a nontoxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a nontoxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxyethylene sorbitol esters, preservatives, flavoradditives such as peppermint oil or saccharin, and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anontoxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Nontoxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also be added.

The following examples will serve to further typify the nature of thepresent invention through the presentation of specific embodiments.These examples should not be construed as a limitation on the scope ofapplicants' invention since the subject matter regarded as the inventionis set forth in the appended claims.

EXAMPLE I Upon boiling a solution of 21.8 g of benzylideneacetoaceticacid ethyl ester and 13.0 g of amidinoacetic acid ethyl ester in ISO mlof ethanol for 2 hours,Z-amino--methyl-4-phenyl-l,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester of melting point l64C (alcohol) is obtained.

Yield: 67% of theory.

EXAMPLE 2 Upon boiling a solution of 24.9 g of2-nitrobenzylideneacetoacetic acid methyl ester and 13.0 g ofamidinoacetic acid ethyl ester in l00 ml of ethanol for l hour,2-amino-6-methyl-4-( Z-nitrophenyl )-l ,4-dihy-,dropyridine-3.S-dicarboxylic acid 3ethyl ester 5- 9 methyl ester ofmelting point 168C (alcohol) is obtained.

Yield; 59% of theory.

EXAMPLE 3 Upon boiling a solution of 24.8 g of2-methoxybenzylideneacetoacetic acid ethyl ester and 13.0 g ofamidinoacetic acid ethyl ester in 150 ml of ethanol for 1 hour.2-amino-6-methyl-4-(2-methoxyphenyl)-1.4-dihydropyridine-3.5dicarboxylic acid diethyl ester of melting point 170C(ethanol) is obtained.

Yield: 65% of theory.

EXAMPLE 4 Upon boiling a solution of 23.2 g of 2methylbcnzylideneacetoacetic acid ethyl ester and 13.0 g of amidinoacetic acidethyl ester in 150 ml of ethanol for 2 hours. 2-amino-6-methyl-4-(Z-methylphenyh-1,4- dihydropyridine-3.5-dicarboxylic aciddiethyl ester of melting point 130C (ethanol) is obtained.

Yield: 71% of theory.

EXAMPLE 5 Upon boiling a solution of 24.3 g of2-cyanobenzylideneacetoaeetic acid ethyl ester and 13.0 g ofamidinoaeetic acid ethyl ester in 100 ml of ethanol for 2 hours.2-amino-6-methyl4-( 2-cyanophenyl)-1,4- dihydropyridine-B,5-dicarboxylicacid diethyl ester of melting point 208C (ethanol) is obtained.

Yield: 54% of theory.

EXAMPLE 6 Upon boiling a solution of 14.2 g of2-trifluoromethylbenzylideneacetoacetie acid ethyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 1 hour,2-amino-6-methyl-4-( 2-trifluoromethy1- phenyl l.4-dihydropyridine-3.S-dicarboxylic acid diethyl ester of melting point156C (ethanol) is obtained.

Yield: 76% of theory.

EXAMPLE 7 Upon boiling a solution of 12.6 g of3-chlorobenzylideneacetoacetic acid ethyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours,2-amino-6-methyl-4-(3-chloropheny1)-1,4-dihydropyridinc-3,5-dicarboxylic acid diethyl ester of melting point 157159C (ethanol) is obtained.

Yield: 62% of theory.

EXAMPLE 8 Upon boiling a solution of 13.2 g of4-methylmercaptobenzylideneacetoacetie acid ethyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 1 hour.2-amino-6-methyl-4-( 4-methylmercaptophenyl l.4-dihydropyridine-3,S-dicarboxylic acid diethyl ester of melting point165C (ethyl acetatelpetroleum ether) is obtained.

Yield: 49% of theory.

EXAMPLE 9 Upon boiling a solution of 26.3 g of3-nitrobenzylideneacetoacetic acid ethyl ester and 13.0 g ofamidinoacetic acid ethyl ester in 200 ml of ethanol for 1 hour,2amino'6-methy1-4-( 3-nitrophenyl 1 .4-dihydropyridine 3.5-dicarboxylicacid diethyl ester of melting point 169C (ethanol) is obtained.

Yield: 58% of theory.

EXAMPLE 10 Upon boiling a solution of 24.9 g of3-nitrobenzylideneacetoacetic acid methyl ester and 13.0 g ofamidinoaeetic acid ethyl ester in 180 ml of ethanol for 1 hour.2-amino-6-methyl-4-( 3-nitrophenyl 1 .4-dihydropyridine3.S-dicarboxylicacid 3-ethyl ester 5- methyl ester of melting point 124C is obtained.

Yield: 59% of theory.

EXAMPLE 1 1 EXAMPLE l2 Boiling a solution of 10.9 g of3-nitrobenzylideneacetoacetic acid propargyl ester and 5.2 g ofamidinoacetic acid ethyl ester in ml of ethanol for 1 hour yields2-amino-6-methyl-4-(3-nitrophenyl)-1 .4-dihydropyridine-B,S-dicarboxylic acid 3-ethyl ester 5- propargyl esterof melting point 181C (ethanol).

Yield: 59% of theory.

EXAMPLE 13 Heating a solution of 14.6 g of 3-nitrobenzylideneacetoaceticacid B-methoxyethyl ester and 6.5 g of amiclinoacetic acid ethyl esterin ml of ethanol for 1 hour yields 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3.5-dicarboxylic acid 3-ethyl ester 5-Bmethoxyethylester of melting point 179C (ethyl acetate/petroleum ether).

Yield: 58% of theory.

EXAMPLE 14 Upon boiling a solution of 7.6 g of 3-nitrobenzaldehyde, 5.0g of acetylaee tone and 6.5 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 2 hours, 2- amino-S-acetyl-6-methyl-4-( 3-nitrophenyll ,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 217C(ethanol) is obtained.

Yield: 48% of theory.

EXAMPLE 15 Upon boiling a solution of 14.2 g of 3-nitro-6-chlorobenzylideneacetoacetic acid methyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 m1 of ethanol for 1 hour,2-amino-6-methyl-4-( 3-nitro-6-chlorophenyl )-1.4-dihydropyridine-3,5-dicarboxylic acid 3- ethyl ester S-methyl esterof melting point 124C (ethanol) is obtained.

Yield: 73% of theory.

EXAMPLE 16 Upon boiling a solution of 10.4 g of2-furfurylideneacetoacetic acid ethyl ester and 6.5 g of amidinoaceticacid ethyl ester in 100 ml of ethanol for 2 hours,2-amino-6-methy1-4-(fur-Z-yl l .4-dihydropyridine-3,S-dicarboxylic aciddiethyl ester of melting point 183C (isopropanol) is obtained.

Yield: 78% of theory.

EXAMPLE 17 Upon boiling a solution of M g of benzylidenebenzoylaceticacid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 150 mlof ethanol for 2 hours, 2- amino-4.6-diphenyll.4-dihydropyridine-3.5-dicarboxylic acid ethyl ester of melting point183C (ethanol) is obtained.

Yield: 48% of theory.

EXAMPLE 18 Upon heating a solution of l5.6 g of ethylideneacetoaceticacid ethyl ester and 13.0 g of amidinoacetic acid ethyl ester in I00 mlof ethanol for 2 hours. 2-amino-4.6-dimethyl-l.4-dihydropyridine- 3.5dicarboxylic acid diethyl ester of melting point 140C (isopropanol) isobtained.

Yield: 59% of theory.

EXAMPLE 19 Upon boiling a solution of 2.8 g of acetaldehyde. 5.6 g ofcyclohexane-l .3dione and 6.5 g of amindinoacetic acid ethyl ester in100 ml of ethanol for 2 hours. 2- amino-4-methyll .4.5,6,7.S-hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester of meltingpoint 236C (ethanol) is obtained.

Yield: 53% of theory.

EXAMPLE 20 Upon boiling a solution of 7.6 g of 3-nitrobenzaldehyde. 5.6g of cyclohexane-l.3-dione and 6.5 g of amidinoacetic acid ethyl esterfor 1 hour. 2-amino-4- (3nitrophenyl l.4.5.6.7.8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 260C is obtained (alcohol/DMF).

Yield: 61% of theory.

EXAMPLE 21 Upon boiling a solution of 7.l g of 3-chlorobenzaldehyde. 5.6g of cyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl esterin 150 ml of ethanol for 2 hours, 2-am'mo-4( 3-chlorophenyl )-l,4.5.6.7.8-hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 266C (ethanol/DMF) is obtained.

Yield: 66% of theory.

EXAMPLE 22 Upon boiling a solution of 5.3 g of pyridin-2-aldehyde. 5.6 gof cyelohexane-l.3-dione and 6.5 g of amidinoacetic acid ethyl ester in150 ml of alcohol for 3 hours. 2-amino-4-( a-pyridyl 1 .4.5.6.7,8-hexahydr0- 5-oxoquinoline-3-carboxylic acid ethyl ester of meltingpoint 260C is obtained (alcohol).

Yield: 46% of theory.

EXAMPLE 23 Upon heating a solution of 7.6 g of 2-nitrobenzaldehyde. 5.6g of cyclohexane-L3-dione and 6.5 g of amidinoacetic acid ethyl ester in100 ml of ethanol for 2 hours. 2-amino-4-( 2-nitrophenyl )-l.4.5.6.7.8-hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 2l2C (alcohol) is obtained.

Yield: 69% of theory.

EXAMPLE 24 Upon heating a solution of 7.9 g of quinolin-4-aldehyde. 5.6g of cyclohexane-l.3-dione and 6.5 g of amidinoacetic acid ethyl esterin 150 ml of ethanol for 12 3 hours. 2-amino-4-( quinol-4-yl l.4.5.6.7.8-hexahydro-S-oxoquinoline-carboxylic acid 3-ethyl ester ofmelting point 260C (ethanol/DMF) is obtained.

Yield: 81% of theory.

EXAMPLE 25 EXAMPLE 26 Upon boiling a solution of 6.3 g ofl-naphthaldehyde. 4.5 g of cyclohexane-l.3-dione and 5.2 g ofamidinoacetic acid ethyl ester in I50 ml of ethanol for 2 hours.2-amino-4-(naphthl-yl l .4.5,6.7.8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 279C(ethanol/DMF) is obtained.

Yield: 64% of theory.

EXAMPLE 27 Upon heating a solution of 6.3 g of isoquinolin-laldehyde.4.5 g of cyclohexane-L3-dione and 5.2 g of amidinoacetie acid ethylester in lOO ml of ethanol for 2 hours. 2-amino-4-( isoquinol-l-yl l.4.5,6.7.8-hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 272C (ethanol) is obtained.

EXAMPLE 28 Upon heating a solution of 4.8 g of 6-methylpyridin-2-aldehyde, 4.5 g of cyclohexanel .3-dione and 5.2 g of amidinoacetieacid ethyl ester in l20 ml of ethanol for 8 hours, 2-amino-4-(6-methylpyrid-2-yl l .45 .6.7.8- hexahydro-S-oxoquinoline-3-carboxylicacid ethyl ester of melting point 260C (ethanol/DMF) is obtained.

Yield: 46% of theory.

EXAMPLE 29 Upon boiling a solution of l3.3 g of 3-nitroben-Zylideneacetoacetic acid ethyl ester and 5.l g of amidinoacetamide inI50 ml of ethanol for 2 hours. 2- amino-6-methyl-5-carbethoxy-4-(3-nitrophenyl l .4- dihydropyridine-3-carboxylic acid amide of meltingpoint 260C (alcohol) is obtained.

Yield; 52% of theory.

EXAMPLE 30 Upon heating a solution of 6.5 g of 2-cyanobenzaldehyde. 5.6g of cyclohexane-l.3-dione and 6.5 g of amidinoaeetic acid ethyl esterin ml of ethanol for 5 hours. 2-amino-4-( Z-cyanophenyl l.4.5.6,7.8-hex'- ahydro-S-oxoquinoline- 3-carboxylic acid ethyl ester ofmelting point C (ethanol) is obtained.

Yield: 49% of theory.

EXAMPLE 3 1 Upon heating a solution of 26.3 g of3-nitrobenzylideneacetoacetic acid ethyl ester and MA g of amidinoaceticacid isopropyl ester in 250 ml of ethanol for 2 hours.2-amino-6-methyl-4-(3-nitrophenyl)-l.4- dihydropyridine-3.5-dicarboxylicacid 3-isopropyl ester S-ethyl ester of melting point l756C (ethanol) isobtained.

13 Yield: 77% of theory.

EXAMPLE 32 Heating a solution of 14.3 g of2-trifluoromethylbenzylideneacetoacetic acid ethyl ester and 7.2 g ofamidinoacetic acid isopropyl ester in 150 ml of ethanol for 1 houryields 2-amino-6-methyl-4-(2-trifluoromethylphenyll,4-dihydropyridine-3,S-dicarboxylic acid 3-isopropyl ester S-ethylester of melting point 106C.

Yield: 49% of theory.

EXAMPLE 33 Upon heating a solution of 13.9 g of3-nitrobenzylideneacetoacetic acid isopropyl ester and 7.2 g ofamidinoacetic acid isopropyl ester in 180 ml of ethanol for 1 hour.2amino-6-methyl-4-(3-nitrophenyl)-1.4- dihydropyridine-3.S-dicarboxylicacid diisopropyl ester of melting point 122C (ether) is obtained.

Yield: 62% of theory.

EXAMPLE 34 Upon boiling a solution of 12.2 g of2-cyanobenzylideneacetoacetic acid ethyl ester and 7.2 g ofamidinoacetic acid isopropyl ester in 200 ml of ethanol for 1 hour,2-amino-6-methyl-4-(2-cyanophenyl)-1.4- dihydropyridine-3,5-dicarboxylieacid 3-isopropyl ester -ethyl ester of melting point 200C (isopropanol)is obtained.

Yield: 58% of theory.

EXAMPLE 35 Upon heating a solution of 12.5 g of3-nitrobenzylideneacetoacetic acid methyl ester and 7.2 g ofamidinoaeetic acid isopropyl ester in 150 ml of ethanol for 2 hours.2-amino-6-methyl-4-(3-nitrophenyl)-1.4- dihydropyridine-3,S-dicarboxylicacid 3-isopropyl ester S-methyl ester of melting point 167C (ethanol) isobtained.

Yield: 82% of theory.

EXAMPLE 36 Upon heating a solution of l 1.0 g of2-trifluoromethyl-4-nitrobenzaldehyde. 5.6 g of cyclohexane- 1 ,3-dioneand 6.5 g of amidinoacetic acid ethyl ester in 250 ml of ethanol of 2hours. 2-amino-4-(2-trifluoromethyl-4-nitrophenyl)-1,4.5.6,7,8-hexahydro-5-oxoquinoline-3- carboxylic acidethyl ester of melting point 264C (ethanol) is obtained.

Yield: 62% of theory.

EXAMPLE 37 Heating a solution of 13.2 g of 3'nitrobenzylideneacetoaceticacid ethyl ester and 7.2 g of amidinoacetic acid n-propyl ester in 200ml of ethanol for 2 hours yields 2-amino-6-methyl-4-( 3-nitrophenyl)-l.4-dihydropyridine-3.5'dicarboxylic acid 3-n-propyl ester 5-ethyl esterof melting point 168C (ethanol).

Yield: 79% of theory.

EXAMPLE 38 Boiling a solution of 8.5 g of 6-nitroveratraldehyde. 4.0 gof cyclohexane-l.3-dione and 5.2 g of amidinoacetic acid ethyl ester in150 ml of ethanol for 1 hour yields 2-amino-4-(2-nitro-4.5-dimethoxyphenyll45.6.7.8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 261C (ethanol).

Yield: 52% of theory.

EXAMPLE 39 EXAMPLE 40 Upon heating a solution of 6.1 g ofbiphenyl-Z-aldehyde, 3.8 g of cyclohexane-L3-dione and 5.1 g ofamidinoacetie acid ethyl ester in m1 of ethanol for 1 hour. 2-amino-4-(biphenyl-2-yl l ,4,5 6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acidethyl ester of melting point 248C (ethanol) is obtained.

Yield: 45% of theory.

EXAMPLE 41 Boiling a solution of 13.4 g of (l-naphthylidene)-acetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl esterin 100 ml of ethanol for 8 hours yields 2-amino-6-methyl-4-(1-naphthyl)- 1 ,4-dihydropyridine-3.5-dicarboxylic acid diethyl ester ofmelting point 174C (ethanol).

Yield: 62% of theory.

EXAMPLE 42 Upon heating a solution of 11.5 g of2-cyanobenzylideneacetoacetic acid methyl ester and 7.2 g ofamidinoacetic acid isopropyl ester in 100 ml of ethanol for 6 hours.2-amino-6-methyl-4-(2-cyanophenyl)-l ,4-dihydropyridine-3.5-dicarboxylic acid 3-isopropyl ester 5-methyl esterof melting point 21 1C (ethanol) is obtained.

Yield: 72% of theory.

EXAMPLE 43 Upon boiling a solution of 11.5 g of2'cyanobenzylideneacetoacetic acid methyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 8 hours,2-amino-6-methyl-4-( 2-cyanophenyl )-l .4-dihydropyridine-3,S-dicarboxylic acid 3-ethyl ester 5- methyl ester ofmelting point 224C (ethanol) is obtained.

Yield: 66% of theory.

EXAMPLE 44 Upon boiling a solution of 14.8 g of2-phenylbenzylideneacetoacetic acid ethyl ester and 6.5 g ofamidinoaeetic acid ethyl ester in 100 ml of ethanol for 8 hours,2-amino-6-methyl-4-( biphenyl-2-yl )-1.4-dihydropyridine-3,S-dicarboxylic acid ethyl ester of melting point182C (ethanol) is obtained.

Yield: 41% of theory.

EXAMPLE 45 Upon heating a solution of 12.5 g of3-nitrobenzylideneacetoacetic acid methyl ester and 7.2 g ofamidinoacetic acid n-propyl ester in 100 ml of ethanol for 6 hours,2-amino-6-methyl-4-(3-nitrophenyl)-l.4- dihydropyridine-3.S-dicarboxylicacid 3-npropyl ester S-methyl ester of melting point C (ethanol) isobtained.

Yield: 69% of theory.

EXAMPLE 46 Upon heating a solution of 12.2 g of (2-thenylidene)acetoacetic acid ethyl ester and 6.5 g of amidinoacetic acidethyl ester in 100 ml of ethanol for 4 hours. 2 amino-6-methyl-4-(2-thenyl 1 .4-dihydropyridine-3.5-dicarboxylic acid diethyl ester ofmelting point 170C (ethanol) is obtained.

Yield: 73% of theory.

EXAMPLE 47 Upon heating a solution of 10.9 g of benzylideneacetoaceticacid dimethylamide and 5.0 g of amidinoacetamide in 100 ml of ethanolfor 8 hours. 2- amino-6-methyl-4-phenyl-5-( N.N-dimethylaminocarbonyl)-1 .4-dihydropyridine-3-carb0xylic acid amide of melting point 236C(ethanol) is obtained.

Yield: 50% of theory.

EXAMPLE 48 Heating a solution of 10.9 g of benzylideneacetoacetic aciddimethylamide and 6.5 g of amidinoacetic acid ethyl ester in 100 ml ofmethanol for 6 hours yields 2-amino-6-methyl-4-phenyll,4-dihydropyridine-3,5- dicarboxylic acid 3-ethy1 esterS-(NN-dimethylamide) of melting point 230C (alcohol).

Yield: 61% of theory.

EXAMPLE 49 Boiling a solution of 13.2 g of 2-nitrobenzylideneaeetoaceticacid ethyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 100ml of ethanol for 6 hours yields 2-amino-6-methy1-4-( 2-nitrophenyl1.4-dihydropyridine 3.5-dicarboxylic acid 3-isopropyl ester S-ethylester of melting point 139C (isopropanol).

Yield: 39% of theory.

EXAMPLE 50 Boiling a solution of 13.2 g of 2-nitrobenzylideneacetoacetic acid ethyl ester and 6.5 g of amidinoacetic acidethyl ester in 100 ml of ethanol for 6 hours yields2-amino-6-methyl-4-(2-nitrophenyl)- l,4-dihydropyridine-3,S-dicarboxylicacid diethyl ester of melting point 159C (ethanol).

Yield: 52% of theory.

EXAMPLE 51 Upon heating a solution of 12.5 g ofZ-nitrobenzylideneacetoacetic acid methyl ester and 7.2 g ofamidinoacetic acid isopropyl ester in 100 ml of ethanol for 8 hours,2-amino-6-methyl-4-(2-nitrophenyl)-l,4- dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester 5-methyl ester of melting point 203C(isopropanol) is obtained.

Yield: 50% of theory.

EXAMPLE 52 Upon heating a solution of 12.2 g of2-cyanobenzylideneacetoacetic acid ethyl ester and 7.2 g ofamidinoacetic acid n-propyl ester in 100 ml of ethanol for 8 hours.2-amino-6-methy1-4-(2-cyanophenyl)-l.4- dihydropyridine-3.5-dicarboxylicacid 3-n-propyl ester S-ethyl ester of melting point 182C (ethanol) isobtained.

Yield: 62% of theory.

EXAMPLE 53 Upon heating a solution of 13.9 g of3nitrobenzylideneacetoacetic acid isopropyl ester and 7.2 g ofamidinoacetic acid n-propyl ester in 100 ml of ethanol for 6 hours.2-amino-6methyl-4-(3-nitrophenyl)-1.4- dihydropyridine-3,5-dicarboxylicacid 3-n-propyl ester S-isopropyl ester of melting point 199C(isopropanol) is obtained.

Yield: of theory.

EXAMPLE 54 Heating a solution of 6.5 g of 3-cyanobenzaldehyde. 5.6 g ofcyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl ester in mlof ethanol for 6 hours yields 2-amino-4-( 3-cyanophenyl l,4.5,6,7,8-hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 262C (ethanol/dimethylformamide).

Yield: 56% of theory.

EXAMPLE 55 Upon heating a solution of 9.3 g of 3-bromobenzaldehyde, 5.6g of cyclohexane-lJ-dione and 6.5 g of amidinoacetic acid ethyl ester in100 ml of ethanol for 8 hours.2-amino-4-(3-bromophenyl)-1,4,5.6.7.8-hexahydro5-oxoquinoline-3-carboxylicacid ethyl ester of melting point 255C (ethanol) is obtained.

Yield: 44% of theory.

EXAMPLE 56 Upon boiling a solution of 9.3 g of 2-bromobenzaldehyde, 5.6g of cyclohexane-L3-dione and 6.5 g of amidinoacetic acid ethyl ester in100 ml of ethanol for 6 hours, 2-1mino-4-( 2-bromophenyl l,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 245C (ethanol) is obtained.

Yield: 46% of theory.

EXAMPLE 57 Upon heating a solution of 8.9 g of 3-carbethoxybenzaldehyde,5.6 g of eyclohexanel ,3-dione and 6.5 g of amidinoacetic acid ethylester in 100 m1 of ethanol for 4 hours, 2-amino-4-( 3-carbethoxyphenyl)-1 4567.8- hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 234C (ethanol) is obtained.

Yield: 54% of theory.

EXAMPLE 58 17 wherein R is hydrogen; lower alkyl; lower alkenyl; loweralkynyl; phenyl; substituted phenyl in which the substituents are one tothree members selected from the group consisting of lower alkyl. loweralkoxy. halogeno, nitro. cyano. trifluoromethyl. azido. carbot loweralkoxy lower alkylsulfonyl. lower alkylsultinyl. lower alkylthio orphenyl; or naphthyl;

R is hydrogen. lower alkyl. phenyl or pyridyl;

R is lower alkoxy. lower alkoxytlower alltoxy). lower alkenyloxy. loweralkynyloxy. amino. lower alkylamino or di(lowcr alkyl )amino; and

R is lower alkoxy. lower alkoxy(lo\ver alkoxy). lower alkenyloxy. loweralkynyloxy, amino. lower alkylamino or di(lo\ver alkyl)amino.

which comprises reacting a dicarbonyl compound of the formula:

COR

wherein R, R and R are as above defined. with an amidine of the formula:

wherein R is as above defined, at a temperature of from C to 250C andrecovering the compound produced.

2. A process according to claim 1 wherein the reaction takes place inthe presence of an inert. organic solvent.

3. A process according to claim 2 wherein the inert organic solvent islower alkenol. an ether, glacial acetic acid. pyridine,dimethylformamide. dimethylsulphoxide or acetonitrile.

4. A process according to claim 2 wherein the reaction is conducted atthe boiling point of the solvent.

5. A process according to claim 4 wherein the reactants are employed insubstantially equimolar amounts.

6. A process according to claim 1 wherein R is lower alkyl or phenyl.

7. A process according to claim 1 wherein R is lower alkyl, naphthyl.phenyl or phenyl substituted with from one to three substituentsselected from the group consisting of lower alkyl, lower alkoxy,halogeno, nitro, cyano. trifluoromethyl. azido. carbo( lower alkoxylower alkylsulfonyl. lower alkylsulfinyl, lower alkylthio or phenyl.

8. The process according to claim 1 for the production of2amino-6-methy|4-( Z-nitrophenyl l .4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester 5- methyl ester which comprises reacting2-nitrobenzylideneacetoacetic acid methyl ester and amidinoacetic acidethyl ester and recovering the compound produced.

9. The process according to claim 1 for the production of2-amino-6-methyl-4-(Z-methylphenyl 1,4- dihydropyridine-3,5dicarboxylicacid diethyl ester which comprises reactingZ-methylbenzylideneacetoacetic acid ethyl ester and amidinoacetic acidethyl ester and recovering the compound produced.

10. The process according to claim 1 for the production of2-amino-6-methyl-4-( 3-chlorophenyl l.4-dihydropyridine3.5-clicarboxylic acid diethyl ester which comprisesreacting 3-chlorobenzylideneacetoacetic acid ethyl ester and amidoaceticacid ethyl ester and recovering the compound produced.

ll. The process according to claim 1 for the production of2-amino-6-methyl-4-(4-methylmercaptophenyl)-l.4-dihydropyridine-3.S-dicarboxylic acid di ethyl ester which comprisesreacting 4-methylmercaptobenzylideneacetoacetic acid ethyl ester andamidinoacetic acid ethyl ester and recovering the compound produced.

12. The process according to claim 1 for the production of2-amino-6-methyl-4-( 3-nitrophenyl l .4-dihydropyridine-3.S-dicarboxylicacid S-ethyl S-isopropyl ester which comprises reactingB-nitrobenzylideneacetoacetic acid isopropyl ester and amidinoaceticacid ethyl ester and recovering the compound produced.

13. The process according to claim I for the production of2-amino-6-methyl-4-( 3-nitrophenyl l ,4-dihydropyridine-3.5-dicarboxylicacid 3-ethyl ester 5-propargyl ester which comprises reacting3-nitrobenzylideneacetoacetic acid propargyl ester and amidinoaceticacid ethyl ester and recovering the compound produced.

14. The process according to claim 1 for the production of2-amino-6-methyl-4-(3-nitro-6-chlorophenyl)-l,4-dihydropyridine-3.S-dicarboxylic acid 3-ethyl ester S-methyl esterwhich comprises reacting 3-nitro-6- chlorobenzylideneacetoacetic acidmethyl ester and amidinoacetic acid ethyl ester and recovering thecompound produced.

15. The process according to claim 1 for the production of2-amino-4,6-diphenyll ,4-dihydropyridine-3 .5- dicarboxylic acid ethylester which comprises reacting benzylidenebenzoylacetic acid ethyl esterand amidinoacetic acid ethyl ester and recovering the compound produced.

16. The process according to claim I for the production of2-amino-4,6-dimethyll .4-dihydropyridine-3 .5- dicarboxylic acid diethylester which comprises reacting ethylideneacetoacetic acid ethyl esterand amidinoacetic acid ethyl ester and recovering the compound produced.

17. The process according to claim 1 for the production of2-amino-6-methyl-5-carbethoxy-4-(3-nitrophenyl)-l.4-dihydropyridine-Ii-carboxylicacid amide which comprises reacting 3-nitrobenzylideneacetoacetic acidethyl ester and amidinoacetamide and recovering the compound produced.

18. The process according to claim 1 for the production of2-amino-6-methyl-4-( 3-nitrophenyl)-1.4-dihydropyridine-3.S-dicarboxylicacid 3-isopropyl ester 5- ethyl ester which comprises reacting3-nitrobenzylideneacetoacetic acid ethyl ester and amidinoacetic acidisopropyl ester and recovering the compound produced.

19. The process according to claim 1 for the production of2-amino-6-methyl-4-( 3-nitrophenyl l .4-dihydropyridine-3.S-dicarboxylicacid 3-( B-methoxyethyl) ester S-ethyl ester which comprises reacting 3-nitrobenzylideneacetic acid ethyl ester and amidinoacetic acidB-methoxyethyl ester and recovering the compound produced.

20. The process according to claim 1 for the production of2-amino-6-methyl-4-( l-naphthyl l .4-dihy- 19dropyridine-3,5-dicarboxylic acid diethyl ester which comprises reactingl-naphthylidene)-acetoacetic acid ethyl ester and amidinoacetic acidethyl ester and recovering the compound produced.

2l. The process according to claim 1 for the production of2-amino-6-methyl-4-(2-cyanophenyl)-1,4-dihydropyridine-3.S-carboxylicacid 3-isopropyl ester 5- methyl ester which comprises reacting2cyanobenzylideneacetoacetic acid methyl ester and amidinoacetic acidisopropyl ester and recovering the compound produced.

22. The process according to claim 1 for the production of2-amino-6-methyl-4-( Z-cyanophenyl l .4-dihydropyridine-3.S-dicarboxylicacid 3-ethyl ester 5- methyl ester which comprises reactingZ-cyanobenzylideneacetoacetic acid methyl ester and amidinoa cetic acidethyl ester and recovering the compound produced.

23. The process according to claim 1 for the production of2-amino-6-methyl-4-( biphenyl-Z-yl l ,4-dihydropyridine-3.S-dicarboxylicacid ethyl ester which comprises reacting Z-phenylbenzylideneacetoaceticacid ethyl ester and amidinoacetic acid ethyl ester and recovering thecompound produced.

24. The process according to claim 1 for the production of2-amino-6-methyl-4-( 3-nitrophenyl )-l .4-dihydropyridine-3,5-carboxylicacid 3-n-propyl ester 5- methyl ester which comprises reacting3-nitrobenzylideneacetoacetic acid methyl ester and amidinoacetic acidn-propyl ester and recovering the compound produced.

25. The process according to claim I for the production of2-amino-6-methyl-4-phenyl-5-(N,N-dimethylaminocarbonyl l,4-dihydropyridine-3-carboxylic acid amide which comprises reactingbenzylideneacetoacetic acid dimethylamide and amidinoacetamide andrecovering the compound produced.

26. The process according to claim 1 for the production of2-amino-o-methyl-4-phenyl-l.4-dihydropyridine-3.5-dicarboxylic acid3-ethyl ester 5-(N,N-dimethylamide) which comprises reactingbenzylideneacetoacetic acid dimethylamide and amidinoacetic acid ethylester and recovering the compound produced.

27. The process according to claim 1 for the production of2amino-6-methyl-4-( Z-nitrophenyl l ,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester 5- ethyl ester which comprises reacting2-nitrobenzylideneacetoacetic acid ethyl ester and amidinoacetic acidisopropyl ester and recovering the compound produced.

28. The process according to claim 1 for the produc tion of2-amino-6-methyl-4-( Z-nitrophenyl l ,4-dihy- 20dropyridine-3.S-dicarboxylic acid 3-isopropyl ester 5' methyl esterwhich comprises reacting Z-nitrobenzylideneacetoacetic acid methyl esterand amidinoacetic acid isopropyl ester S-methyl ester and recovering thecompound produced.

29. The process according to claim 1 for the production of2-amino-6-methy'1 4-(2-cyanophenyl)-1,4-dihydropyridine-3.S-dicarboxylicacid 3-n-propyl ester 5- cthyl ester which comprises reactingZ-cyanobenzylideneacetoacetic acid ethyl ester and amidinoacetic acidn-propyl ester and recovering the compound produced.

30. The process according to claim 1 for the production of2-amino-6-methyl-4-( 3-nitrophenyl l .4-dihydropyridine-3,5-dicarboxylicacid 3-n-propyl ester 5- isopropyl ester which comprises reacting3-nitrobenzylideneacetoacetic acid isopropyl ester and amidinoaceticacid n-propyl ester and recovering the compound produced.

31. The process according to claim 1 for the production of2-amino-6-methyl-4-( 2-trifluoromethylphenyll.4-dihydropyridine-3.5-carboxylic acid 3-isopropyl ester S-ethyl esterwhich comprises reacting Z-trifluoromethylbenzylideneacetoacetic acidethyl ester and amidinoacetic acid isopropyl ester and recovering thecompound produced.

32. The process according to claim 1 for the production of2-amino-6-methyl-4-( 3-nitrophenyl l .4-dihydropyridine-3,S-dicarboxylicacid diisopropyl ester which comprises reacting 3-nitrobenzylideneacetoacetic acid isopropyl ester and amidinoacetic acid isopropyl ester andrecovering the compound produced.

33. The process according to claim 1 for the production of2-amino-6-methyl 4-( Z-cyanophenyl l ,4-dihydropyridine-B.S-dicarboxylicacid 3-isopropyl ester 5- ethyl ester which comprises reactingZ-cyanobenzylideneacetoacetic acid ethyl ester and amidinoacetic acidisopropyl ester and recovering the compound produced.

34. The process according to claim 1 for the production of2-amino-6-methyl-4-( 3-nitrophenyl )-l ,4-dihydropyridine-3.S-carboxylicacid 3-isopropyl ester 5- rnethyl ester which comprises reacting3-nitrobenzylideneacetoacetic acid methyl ester and amidinoacetic acidisopropyl ester and recovering the compound produced.

35. The process according to claim 1 for the production of2-amin0-6-methyl-4-( 3-nitrophenyl l ,4-dihydropyridine-3.S-dicarboxylicacid 3-n-propyl ester 5- ethyl ester which comprises reacting3-nitrobenzylideneacetoacetic acid ethyl ester and amidinoacetic acidn-propyl ester and recovering the compound produced.

1. A PROCESS FOR THE PRODUCTION OF A COMPOUND OF THE FORMULA:
 2. Aprocess according to claim 1 wherein the reaction takes place in thepresence of an inert, organic solvent.
 3. A process according to claim 2wherein the inert organic solvent is lower alkenol, an ether, glacialacetic acid, pyridine, dimeThylformamide, dimethylsulphoxide oracetonitrile.
 4. A process according to claim 2 wherein the reaction isconducted at the boiling point of the solvent.
 5. A process according toclaim 4 wherein the reactants are employed in substantially equimolaramounts.
 6. A process according to claim 1 wherein R is lower alkyl orphenyl.
 7. A process according to claim 1 wherein R is lower alkyl,naphthyl, phenyl or phenyl substituted with from one to threesubstituents selected from the group consisting of lower alkyl, loweralkoxy, halogeno, nitro, cyano, trifluoromethyl, azido, carbo(loweralkoxy), lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio orphenyl.
 8. The process according to claim 1 for the production of2-amino-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester 5-methyl ester which comprises reacting2-nitrobenzylideneacetoacetic acid methyl ester and amidinoacetic acidethyl ester and recovering the compound produced.
 9. The processaccording to claim 1 for the production of2-amino-6-methyl-4-(2-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester which comprises reacting2-methylbenzylideneacetoacetic acid ethyl ester and amidinoacetic acidethyl ester and recovering the compound produced. .
 10. The processaccording to claim 1 for the production of2-amino-6-methyl-4-(3-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester which comprises reacting3-chlorobenzylideneacetoacetic acid ethyl ester and amidoacetic acidethyl ester and recovering the compound produced.
 11. The processaccording to claim 1 for the production of2-amino-6-methyl-4-(4-methylmercaptophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester which comprises reacting4-methylmercaptobenzylideneacetoacetic acid ethyl ester andamidinoacetic acid ethyl ester and recovering the compound produced. 12.The process according to claim 1 for the production of2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl 5-isopropyl ester which comprises reacting3-nitrobenzylideneacetoacetic acid isopropyl ester and amidinoaceticacid ethyl ester and recovering the compound produced.
 13. The processaccording to claim 1 for the production of2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester 5-propargyl ester which comprises reacting3-nitrobenzylideneacetoacetic acid propargyl ester and amidinoaceticacid ethyl ester and recovering the compound produced.
 14. The processaccording to claim 1 for the production of2-amino-6-methyl-4-(3-nitro-6-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester which comprisesreacting 3-nitro-6-chlorobenzylideneacetoacetic acid methyl ester andamidinoacetic acid ethyl ester and recovering the compound produced. 15.The process according to claim 1 for the production of2-amino-4,6-diphenyl-1,4-dihydropyridine-3,5-dicarboxylic acid ethylester which comprises reacting benzylidenebenzoylacetic acid ethyl esterand amidinoacetic acid ethyl ester and recovering the compound produced.16. The process according to claim 1 for the production of2-amino-4,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethylester which comprises reacting ethylideneacetoacetic acid ethyl esterand amidinoacetic acid ethyl ester and recovering the compound produced.17. The process according to claim 1 for the production of2-amino-6-methyl-5-carbethoxy-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid amide which comprises reaCting3-nitrobenzylideneacetoacetic acid ethyl ester and amidinoacetamide andrecovering the compound produced.
 18. The process according to claim 1for the production of2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester 5-ethyl ester which comprises reacting3-nitrobenzylideneacetoacetic acid ethyl ester and amidinoacetic acidisopropyl ester and recovering the compound produced.
 19. The processaccording to claim 1 for the production of2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-( Beta -methoxyethyl) ester 5-ethyl ester which comprisesreacting 3-nitrobenzylideneacetic acid ethyl ester and amidinoaceticacid Beta -methoxyethyl ester and recovering the compound produced. 20.The process according to claim 1 for the production of2-amino-6-methyl-4-(1-naphthyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester which comprises reacting(1-naphthylidene)-acetoacetic acid ethyl ester and amidinoacetic acidethyl ester and recovering the compound produced.
 21. The processaccording to claim 1 for the production of2-amino-6-methyl-4-(2-cyanophenyl)-1,4-dihydropyridine-3,5-carboxylicacid 3-isopropyl ester 5-methyl ester which comprises reacting2-cyanobenzylideneacetoacetic acid methyl ester and amidinoacetic acidisopropyl ester and recovering the compound produced.
 22. The processaccording to claim 1 for the production of2-amino-6-methyl-4-(2-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester 5-methyl ester which comprises reacting2-cyanobenzylideneacetoacetic acid methyl ester and amidinoacetic acidethyl ester and recovering the compound produced.
 23. The processaccording to claim 1 for the production of2-amino-6-methyl-4-(biphenyl-2-yl)-1,4-dihydropyridine-3,5-dicarboxylicacid ethyl ester which comprises reacting 2-phenylbenzylideneacetoaceticacid ethyl ester and amidinoacetic acid ethyl ester and recovering thecompound produced.
 24. The process according to claim 1 for theproduction of2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-carboxylicacid 3-n-propyl ester 5-methyl ester which comprises reacting3-nitrobenzylideneacetoacetic acid methyl ester and amidinoacetic acidn-propyl ester and recovering the compound produced.
 25. The processaccording to claim 1 for the production of2-amino-6-methyl-4-phenyl-5-(N,N-dimethylaminocarbonyl)-1,4-dihydropyridine-3-carboxylic acid amide which comprises reacting benzylideneacetoaceticacid dimethylamide and amidinoacetamide and recovering the compoundproduced.
 26. The process according to claim 1 for the production of2-amino-6-methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid3-ethyl ester 5-(N,N-dimethylamide) which comprises reactingbenzylideneacetoacetic acid dimethylamide and amidinoacetic acid ethylester and recovering the compound produced.
 27. The process according toclaim 1 for the production of2-amino-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester 5-ethyl ester which comprises reacting2-nitrobenzylideneacetoacetic acid ethyl ester and amidinoacetic acidisopropyl ester and recovering the compound produced.
 28. The processaccording to claim 1 for the production of2-amino-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester 5-methyl ester which comprises reacting2-nitrobenzylideneacetoacetic acid methyl ester and amidinoacetic acidisopropyL ester 5-methyl ester and recovering the compound produced. 29.The process according to claim 1 for the production of2-amino-6-methyl-4-(2-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-n-propyl ester 5-ethyl ester which comprises reacting2-cyanobenzylideneacetoacetic acid ethyl ester and amidinoacetic acidn-propyl ester and recovering the compound produced.
 30. The processaccording to claim 1 for the production of2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-n-propyl ester 5-isopropyl ester which comprises reacting3-nitrobenzylideneacetoacetic acid isopropyl ester and amidinoaceticacid n-propyl ester and recovering the compound produced.
 31. Theprocess according to claim 1 for the production of2-amino-6-methyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-carboxylic acid 3-isopropyl ester 5-ethyl ester which comprisesreacting 2-trifluoromethylbenzylideneacetoacetic acid ethyl ester andamidinoacetic acid isopropyl ester and recovering the compound produced.32. The process according to claim 1 for the production of2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diisopropyl ester which comprises reacting3-nitrobenzylideneacetoacetic acid isopropyl ester and amidinoaceticacid isopropyl ester and recovering the compound produced.
 33. Theprocess according to claim 1 for the production of2-amino-6-methyl-4-(2-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester 5-ethyl ester which comprises reacting2-cyanobenzylideneacetoacetic acid ethyl ester and amidinoacetic acidisopropyl ester and recovering the compound produced.
 34. The processaccording to claim 1 for the production of2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-carboxylicacid 3-isopropyl ester 5-methyl ester which comprises reacting3-nitrobenzylideneacetoacetic acid methyl ester and amidinoacetic acidisopropyl ester and recovering the compound produced.
 35. The processaccording to claim 1 for the production of2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-n-propyl ester 5-ethyl ester which comprises reacting3-nitrobenzylideneacetoacetic acid ethyl ester and amidinoacetic acidn-propyl ester and recovering the compound produced.